The present invention relates to composite hydrogels for delivery of biologically active materials, and more specifically to compositions comprising hydrogel forming triblock copolymers and drug loaded micelles of diblock copolymers.
One of the major problems in the development of anticancer drug formulations is the delivery of the drugs with adequately high bioavailability for therapeutic intention. As many anticancer agents are hydrophobic, clinical administration of these drugs typically requires dissolution using organic solvents. One such agent is paclitaxel, which is a widely used small molecular drug effective against an extensive range of solid tumors. However, its clinical applications have been mostly impeded by its extremely low aqueous solubility (0.3 micrograms/mL in water), which limits its administration to the use of a formulation comprising of 50:50 mixture of Cremophor EL (polyethoxylated castor oil):ethanol. Although this formulation is able to increase the solubility and bioavailability of paclitaxel (PTX), it can also lead to hypersensitivity reactions and other severe side effects in some cases. Despite premedication with corticosteroids to reduce the immune response, minor reactions such as rashes and flushing still occur in 41% to 44% of patients and potentially fatal reactions occur in 1.5% to 3% of patients. Thus, additional materials and methods are needed for administering hydrophobic drugs.
Hydrogels have emerged as an important class of materials for biomedical applications due to their unique properties that bridge the gap between solid and liquid states. Amongst the numerous classes of synthetic polymeric materials that are capable of forming hydrogels, ABA-type amphiphilic triblock copolymers have a hydrophilic central B block flanged on both the ends by peripheral hydrophobic A blocks. These materials are of interest because they can potentially form physical gels that do not involve the formation of covalent bonds. In some instances, the self-assembled morphology can change from independent micelles to a network of bridged micelles, and eventually to a hydrogel network at higher polymer concentration.
Owing to their non-toxicity and biocompatibility, poly(ethylene glycol) (PEG) has been used extensively as the non-ionic hydrophilic B block in hydrogel forming ABA triblock copolymers. Homo- or copolymers of poly(lactides) and poly(caprolactone) have been used for the hydrophobic A blocks. A drawback of the reported triblock copolymers is the high concentration and hydrophobic content needed for hydrogel formation. For example, gelation of an aqueous mixture of poly(L-lactide)-b-poly(ethylene glycol)-b-poly(L-lactide) (PLLA-b-PEG-b-PLLA) triblock copolymer occurs at a polymer concentration of about 16 wt % (weight percent) based on total weight of the aqueous mixture. The hydrophobic block content of the triblock copolymer was in a range of about 17 wt % to 37 wt % based on total weight of the triblock copolymer.
For many biomedical applications, it would be desirable to have polymeric materials that can form hydrogels at a lower concentration, which can be utilized for the delivery of biologically active substances that include hydrophobic drugs.